T-cell epitope discovery and single-cell technologies to advance food allergy research
Authors: Sloan A. Lewis, Bjoern Peters
Journal: Journal of Allergy and Clinical Immunology (2022)

There is good evidence for a role of T cells in food allergy, but there is a lack of mechanistic understanding and phenotypic markers of the specific T cells contributing to pathology. Recent technologic advancements have allowed for a new experimental paradigm where we can find and pull out rare antigen-specific T cells and characterize them at the single-cell level. However, studies in infectious disease and broader allergy have shown that these techniques benefit greatly from precisely defined T-cell epitopes. Food allergens have fewer epitopes currently available, but it is growing and promises to overcome this gap. With growing use of this experimental design, it will be important to unbiasedly map T-cell phenotypes across food allergy and look for commonalities and contrasts to other allergic and infectious diseases. Once a pathologic phenotype for T cells has been established, the frequencies of these cells can be monitored with simpler techniques that could be applied to the clinic and used in diagnosis, prediction of treatment responsiveness, and discovery of targets for new treatments. There is good evidence for a role of T cells in food allergy, but there is a lack of mechanistic understanding and phenotypic markers of the specific T cells contributing to pathology. Recent technologic advancements have allowed for a new experimental paradigm where we can find and pull out rare antigen-specific T cells and characterize them at the single-cell level. However, studies in infectious disease and broader allergy have shown that these techniques benefit greatly from precisely defined T-cell epitopes. Food allergens have fewer epitopes currently available, but it is growing and promises to overcome this gap. With growing use of this experimental design, it will be important to unbiasedly map T-cell phenotypes across food allergy and look for commonalities and contrasts to other allergic and infectious diseases. Once a pathologic phenotype for T cells has been established, the frequencies of these cells can be monitored with simpler techniques that could be applied to the clinic and used in diagnosis, prediction of treatment responsiveness, and discovery of targets for new treatments. Food allergy is prevalent in developed countries (affecting 5%-10% of the population), and its incidence has risen in recent years.1Yu W. Freeland D.M.H. Nadeau K.C. Food allergy: immune mechanisms, diagnosis and immunotherapy.Nat Rev Immunol. 2016; 16: 751-765Crossref PubMed Scopus (365) Google Scholar, 2Koplin J.J. Mills E.N. Allen K.J. 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The year in food allergy.J Allergy Clin Immunol. 2022; 149: 867-873Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Thus, we need improved approaches to diagnose and treat food allergy, which will require a better understanding of the immunologic mechanisms involved. Food allergies are broadly characterized as IgE-mediated, non–IgE-mediated, or mixed IgE- and non–IgE-mediated.1Yu W. Freeland D.M.H. Nadeau K.C. Food allergy: immune mechanisms, diagnosis and immunotherapy.Nat Rev Immunol. 2016; 16: 751-765Crossref PubMed Scopus (365) Google Scholar Antigen-specific T cells evidently play a role in both sensitization and tolerance to food allergens in both IgE and non–IgE-mediated forms of disease.10Saidova A. Hershkop A.M. Ponce M. Eiwegger T. Allergen-specific T cells in IgE-mediated food allergy.Arch Immunol Ther Exp (Warsz). 2018; 66: 161-170Crossref PubMed Scopus (24) Google Scholar It has been shown that during IgE-mediated food allergy, antigen-specific CD4+ T cells are skewed toward a TH2 phenotype. These TH2 cells can produce cytokines (IL-4, IL5, and IL-13) that lead to B-cell production of IgE and additionally cause degranulation of mast cells, basophils, and eosinophils, resulting in allergy symptoms and, in severe cases, anaphylaxis. Non–IgE-mediated food allergy is less common, but its mechanisms are thought to be mediated by allergen-specific T cells.11Nowak-Wegrzyn A. Katz Y. Mehr S.S. Koletzko S. Non-IgE-mediated gastrointestinal food allergy.J Allergy Clin Immunol. 2015; 135: 1114-1124Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar,12Morita H. Nomura I. Orihara K. Yoshida K. Akasawa A. 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With this being said, the best molecularly defined antigens are specific peptide epitopes that can be reproducibly synthesized and delivered as individual peptides, peptide pools, or the payload of MHC-multimers. The benefit of using peptide epitopes over crude extracts when characterizing antigen-specific T-cell responses has been demonstrated in studies of infectious disease and nonfood allergy, as it allows us to pull apart T-cell populations reacting to different targets.19Newell E.W. Davis M.M. Beyond model antigens: high-dimensional methods for the analysis of antigen-specific T cells.Nat Biotechnol. 2014; 32: 149-157Crossref PubMed Scopus (112) Google Scholar Complementing these well-established approaches with antigen-specific cell selection and downstream genomics applications allows for the generation of large data sets and a wealth of knowledge. 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Cantrell J.R. et al.The Immune Epitope Database (IEDB): 2018 update.Nucleic Acids Res. 2019; 47: D339-D343Crossref PubMed Scopus (956) Google ScholarView Large Image Figure ViewerDownload Hi-res image Download (PPT) The combined availability of epitopes and advancements in assays have already led to the discovery of new T-cell subsets in the context of food allergy (Table I20Archila L.D. Chow I.T. McGinty J.W. Renand A. Jeong D. Robinson D. et al.Ana o 1 and Ana o 2 cashew allergens share cross-reactive CD4(+) T cell epitopes with other tree nuts.Clin Exp Allergy. 2016; 46: 871-883Crossref PubMed Scopus (25) Google Scholar,51Srivastava K.D. Qu C. Zhang T. Goldfarb J. Sampson H.A. Li X.M. Food Allergy Herbal Formula-2 silences peanut-induced anaphylaxis for a prolonged posttreatment period via IFN-gamma-producing CD8+ T cells.J Allergy Clin Immunol. 2009; 123: 443-451Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 52Yu W. Zhou X. Dunham D. Lyu S.C. Manohar M. 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